Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key feature in the malignant behavior of glioblastoma is the tendency to invade host brain tissue surrounding the primary tumor site. Several members of the matrix metalloproteinase family are thought to contribute to this invasive capacity. A single nucleotide polymorphism has been described in the matrix metalloproteinase-1 (MMP-1) promoter that consists of either the presence or absence of a guanine nucleotide at position -1607. The presence of the guanine base creates a functional binding site for members of the ETS family of transcription factors and has been shown to increase MMP-1 transcription. The purpose of our study was to characterize this polymorphism in human glioblastoma. Promoter genotyping was performed on brain tumor tissue obtained from 81 patients and compared to 57 healthy individuals. The 2G/2G genotype is more prevalent in glioblastoma tissue compared to healthy individuals (p = 0.01). mRNA and protein expression were measured in a subset of brain tumor and normal brain tissue samples. MMP-1 protein levels are significantly higher in glioblastoma tissue compared to normal brain (p = 0.001). Electromobility shift assays and promoter assays were performed to assess binding capability and transcriptional activity, respectively. Proteins present in glioma cell lines can specifically bind the 2G promoter probe. MMP-1 transcription is significantly higher in cells transfected with the 2G promoter when compared to cells transfected with the 1G promoter (p<0.02). This polymorphism may provide a mechanism for increased expression of MMP-1 in malignant gliomas via elevation of MMP-1 mRNA transcription and may underlie the invasive phenotype.
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PMID:Association of a single nucleotide polymorphism in the matrix metalloproteinase-1 promoter with glioblastoma. 1595 63

Glioma cell-surface binding to hyaluronan (HA), a major constituent of the brain extracellular matrix (ECM) environment, is regulated through a complex membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction that takes place at the leading edges of invading cells. In the present study, intracellular transduction pathways required for the HA-mediated recognition by infiltrating glioma cells in brain was investigated. We show that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression and triggered CD44 shedding from the U-87 glioma cell surface. This potential implication in cerebral metastatic processes was also observed in cells overexpressing the full-length recombinant MT1-MMP, while the overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to do so. This suggests that the cytoplasmic domain of MT1-MMP transduces intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a green tea catechin with anti-MMP and anti-angiogenesis activities, antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely, overexpression of recombinant ROK stimulated CD44 release. Taken together, our results suggest that RhoA/ROK intracellular signaling regulates MT1-MMP-mediated CD44 recognition of HA. These molecular processes may partly explain the diffuse brain-infiltrating character of glioma cells within the surrounding parenchyma and thus be a target for new approaches to anti-tumor therapy.
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PMID:Probing the infiltrating character of brain tumors: inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg. 1599 76

Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1alpha (SDF-1alpha, CXCL12), on the response of human glioma cells. We found that SDF-1alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.
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PMID:The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. 1603 74

The chemokine GRO-alpha (CXCL1) has been found to mediate the proliferation of glia progenitor cells during neural development. As malignant gliomas are thought to arise from glia progenitors or their differentiated counterparts, astrocytes or oligodendrocytes, we have investigated whether GRO-alpha regulates the tumor characteristics of glioma cells. We found first that resected glioma specimens were strongly immunoreactive for GRO-alpha expression in cells with the morphology of tumor cells. In culture, the U251 glioma line transfected to overexpress GRO-alpha had elevated levels of motility and invasiveness. GRO-alpha transfectants increased their expression of several proteins associated with migratory behavior, including matrix metalloproteinase-2, beta1-integrin and SPARC. The implantation of GRO-alpha glioma clones into the brain of nude mice caused the early demise of mice and this was associated with the formation of larger intracerebral tumors when compared with mice implanted with vector control lines. These results implicate GRO-alpha in gliomas and suggest that the dysregulation of a glia proliferative factor contributes to tumorigenesis. Targeting GRO-alpha may be a useful therapeutic tool to control brain tumor biology.
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PMID:The chemokine GRO-alpha (CXCL1) confers increased tumorigenicity to glioma cells. 1603 75

Aberrant expression of matrix metalloproteinase-9 (MMP-9) is implicated in the process of invasion and angiogenesis of malignant tumors as well as in inflammatory diseases of the CNS. Therefore, the development of compounds that can inhibit or suppress MMP-9 is required to treat brain tumors. We investigated the effects of a ginseng saponin metabolite, compound K (20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol), on MMP-9 expression in human astroglioma cells. Compound K significantly inhibited the secretion and protein expression of MMP-9 induced by PMA. The inhibitory effect of compound K on MMP-9 expression correlated with decreased MMP-9 mRNA levels and suppression of MMP-9 promoter activity. The compound K-mediated inhibition of MMP-9 gene expression appears to occur via AP-1 because its DNA-binding and transcriptional activities were suppressed by the agent. Furthermore, compound K significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of AP-1. Finally, compound K inhibited the in vitro invasiveness of glioma cells. Therefore, inhibition of MMP-9 expression by compound K might have therapeutic potential for controlling the growth and invasiveness of brain tumors.
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PMID:Ginseng saponin metabolite suppresses phorbol ester-induced matrix metalloproteinase-9 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathways in human astroglioma cells. 1604 64

Emodin, an inhibitor of protein tyrosine kinase, possesses antiviral, immunosuppressive, anti-inflammatory and anticancer effects. In the present study, we investigated the effect of emodin on the hyaluronic acid (HA)-induced invasion of human glioma cells. Emodin significantly inhibited the HA-induced invasion through a Matrigel coated chamber, secretion of matrix metalloproteinase (MMP)-2, and HA-induced secretion of MMP-9 in glioma cells. To investigate the possible mechanisms involved in these events, we performed Western blot analysis using phospho-specific antibodies, and found that emodin inhibited phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK) 1/2 and Akt/PKB; emodin also suppressed the transcriptional activity of two transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), in glioma cells. In addition, oral administration of emodin suppressed in vivo MMP secretion by glioma tumors in nude mice. Taken together, our results indicate that emodin can effectively inhibit HA-induced MMP secretion and invasion of glioma through inhibition of FAK, ERK1/2 and Akt/PKB activation and partial inhibition of AP-1 and NF-kappaB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.
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PMID:Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. 1607 36

The abnormal expression of matrix metalloproteinases (MMPs) plays an important role in the invasion of malignant gliomas into the surrounding normal brain tissue. This study showed that curcumin has broad-spectrum inhibitory activity against MMP gene expression in human astroglioma cells. RNase protection assay showed that curcumin inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14. Curcumin repressed the DNA binding and transcriptional activities of AP-1, which is a common upstream modulator of MMP-1, -3, and -9 gene expression. In addition, curcumin suppressed the PMA-induced MAP kinase activities, which were differentially involved in modulating the MMPs. This suggests that the inhibition of MMP transcriptions by curcumin is mediated at least in part through the AP-1 and MAP kinase pathways. Curcumin was also found to significantly repress the in vitro invasion of glioma cells. Therefore, the broad-spectrum inhibition of MMP gene expression by curcumin might provide a novel therapeutic strategy for treating gliomas.
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PMID:Curcumin is a potent broad spectrum inhibitor of matrix metalloproteinase gene expression in human astroglioma cells. 1619 11

Host antiangiogenesis factors defend against tumor growth. The matricellular protein, thrombospondin-2 (TSP-2), has been shown to act as an antiangiogenesis factor in a carcinogen-induced model of skin cancer. Here, using an in vivo malignant glioma model in which the characteristics of the tumors formed after intracerebral implantation of GL261 mouse glioma cells are assessed, we found that tumor growth and microvessel density were significantly enhanced in tumors propagated in TSP-2(-/-) mice. Mechanistically, matrix metalloproteinase (MMP)-2 has been associated with neoangiogenesis and it has been proposed that the levels of available MMP-2 may be down-regulated by formation of a complex with TSP-2 that is internalized by low-density lipoprotein receptor-related protein 1 (LRP1). We found elevated expression of MMP-2 and MMP-9 in tumors propagated in TSP-2(-/-) mice, with a preferential localization in the microvasculature. In wild-type mice, MMP-2 was coexpressed with TSP-2 in the tumor microvasculature. In vitro, addition of recombinant (rec) TSP-2 to mouse brain microvessel endothelial cells reduced MMP-2 levels and invasion through mechanisms that could be inhibited by a competitive inhibitor of ligand binding to LRP1 or by siLRP1. Thus, the antiangiogenic activity of TSP-2 is capable of inhibiting the growth of gliomas in part by reducing the levels of MMP-2 in the tumor microvasculature. This mechanism is mediated by LRP1.
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PMID:Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model. 1623 Mar 96

Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To assess the effects of TIMP-3 gene transfer to glioma cells, a replication-defective adenovirus encoding TIMP-3 (Ad.TIMP-3) was employed. Ad.TIMP-3 infection of a panel of glioma cell cultures decreased the proliferative capacity of these cells and induced morphologic changes characteristic for apoptosis. Next, a conditionally replicating adenovirus encoding TIMP-3 was constructed by inserting the TIMP-3 expression cassette into the E3 region of the adenoviral backbone containing a 24-bp deletion in E1A. This novel oncolytic adenovirus, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-3 was shown in s.c. glioma xenografts. The functional activity of TIMP-3 was imaged noninvasively using a near-IR fluorescent MMP-2-activated probe. Tumoral MMP-2 activity was significantly reduced by 58% in the AdDelta24TIMP-3-treated tumors 24 hours after infection. A study into the therapeutic effects of combined oncolytic and antiproteolytic therapy was done in both a s.c. and an intracranial model for malignant glioma. Treatment of s.c. (U-87MG) or intracranial (U-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent.
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PMID:Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma. 1623 Apr 3

Invasion of glioma cells involves the attachment of invading tumor cells to extracellular matrix (ECM), disruption of ECM components, and subsequent cell penetration into adjacent brain structures. Discoidin domain receptor 1 (DDR1) tyrosine kinases constitute a novel family of receptors characterized by a unique structure in the ectodomain (discoidin-I domain). These cell surface receptors bind to several collagens and facilitate cell adhesion. Little is known about DDR1 expression and function in glioblastoma multiforme. In this study we demonstrate that DDR1 is overexpressed in glioma tissues using cDNA arrays, immunohistochemistry and Western blot analysis. Functional comparison of two splice variants of DDR1 (DDR1a and DDR1b) reveal novel differences in cell based glioma models. Overexpression of either DDR1a or DDR1b caused increased cell attachment. However, glioma cells overexpressing DDR1a display enhanced invasion and migration. We also detect increased levels of matrix metalloproteinase-2 in DDR1a overexpressing cells as measured by zymography. Inhibition of MMP activity using MMP inhibitor suppressed DDR1a stimulated cell-invasion. Similarly, an antibody against DDR1 reduced DDR1a mediated invasion as well as the enhanced adhesion of DDR1a and DDR1b overexpressing cells. These results suggest that DDR1a plays a critical role in inducing tumor cell adhesion and invasion, and this invasive phenotype is caused by activation of matrix metalloproteinase-2.
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PMID:Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. 1623 85


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